Dietary Cannabidiol Activates PKA/AMPK Signaling and Attenuates Chronic Inflammation and Leaky Gut in DSS‐Induced Colitis Mice

Scope Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut, accompanied by impaired epithelial integrity, increased macrophage infiltration, and enhanced colon cancer risk. Methods and Results Cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, is supplemented into mice diet, and its beneficial effects against dextran sulfate sodium (DSS)‐induced experimental colitis is evaluated. Eight‐week‐old mice were fed a standard diet supplemented with or without CBD (200 mg kg‐1) for 5 weeks. In the 4th week of dietary treatment, mice were subjected to 2.5% DSS induction for 7 days, followed by 7 days of recovery, to induce colitis. CBD supplementation reduced body weight loss, gross bleeding, fecal consistency, and disease activity index. In addition, CBD supplementation protected the colonic structure, promoted tissue recovery, and ameliorated macrophage infiltration in the colonic tissue, which was associated with the activation of cyclic AMP‐protein kinase A, extracellular signal‐regulated kinase ½, and AMP‐activated protein kinase signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and related pro‐inflammatory marker secretion. Consistently, CBD feeding reduced tight junction protein claudin2 and myosin light chain kinase in DSS‐treated mice. Conclusion Dietary CBD protects against inflammation and colitis symptoms induced by DSS, providing an alternative approach to IBD management. Cannabidiol (CBD) supplementation reduced disease activity indexes in dextran sulfate sodium‐induced colitis mice and protected the colonic structure and ameliorated mucosal damage and macrophage infiltration, which is associated with activated cyclic AMP‐protein kinase A (PKA), extracellular signal‐regulated kinase (ERK) ½, and AMP‐activated protein kinase (AMPK) signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and tight junction protein claudin2 and myosin light chain kinase in colon, correlated with activated signaling pathways.